TB remains the greatest cause of death in the world from any single infectious disease. Advances in mycobacterial molecular genetics have culminated in establishing the genome sequence of M. tuberculosis H37Rv, making it possible to generate a vast new repertoire of potential preventive or therapeutic TB vaccine candidates. DNA vaccination is an alternative means of generating endogenous antigen. The long term objectives of this component are to develop a TB vaccine that can be used to protect human subjects, as well as nonhuman primates, and to develop a therapy for treating active cases. Toward that goal, we will develop a nonhuman primate model for research on TB immunopathology and pre-clinical testing of TB vaccines and therapeutics. The specific aims are to establish a nonhuman primate model for tuberculosis that mimics clinical, bacteriological, and immunological characteristics of human disease; to determine the immunogenicity and protection of a new candidate vaccine (DNA-hsp65 gene vaccine) in monkeys; and to determine the therapeutic effectiveness of the DNA-hsp65 gene vaccine in monkeys with active tuberculosis. Experimentally infected Chinese-origin rhesus macaques, cynomolgus macaques and baboons will be assessed clinically, immunologically, and pathologically for similarities to and differences from human TB disease progression. Based on the results, one of these species will be subjected to a pre-exposure vaccine trial to test efficacy of the DNA-hsp65 gene vaccine to prevent infection; and to a post-exposure trial to test efficacy of the vaccine to treat infection. The development of a nonhuman primate model for tuberculosis will help us understand the disease process and outcome, and will enable experimental tuberculosis in a nonhuman primate to be compared with the human disease in regard to immune alterations and surrogate markers occurring during infection and vaccine/therapy. Finally, the proposed work will establish a nonhuman primate model for tuberculosis for understanding disease progression, identifying immunological alterations, and developing safe and effective methods for preventing and treating tuberculosis.